Project Summary This K08 application is for Dr. Jennifer McIntosh, an assistant professor of Maternal Fetal Medicine at the Medical College of Wisconsin who is building her research niche as a physician-scientist studying mitochondrial dysfunction within the human placenta as a mechanism for preeclampsia. This award would afford Dr. McIntosh the time and resources that she needs to develop the research project and collaborative relationships. She has established mentoring and consultative teams that include Dr. David Gutterman, an expert in human vascular reactivity in the microcirculation, Dr. Hartmut Weiler, an expert in cellular and molecular mechanisms relating to coagulation and placental development, Dr. Allen Cowley, an integrative physiologist internationally recognized for his research in hypertension, and Dr. Nicole Lohr, an expert in vascular biology and experience with the placental vasculature. Dr. McIntosh has also woven in experience with outside institutions to gain expertise in cutting edge placental techniques as well as mitochondrial next generation sequencing to ensure she achieves her career development goals and research aims. Preeclampsia remains a worldwide problem with over 10 million pregnant women impacted and over half a million perinatal lives lost annually. Preeclampsia is on the rise, and the underlying pathophysiological mechanism of preeclampsia remains poorly understood. Vascular dysfunction and endothelial damage within the placenta and maternal vasculature contribute to hypertensive disorders of pregnancy. A novel relationship may exist between mitochondrial damage and endothelial dysfunction and subsequent development of preeclampsia. The overall hypothesis is that with decreased placental perfusion, ischemia results in increased reactive oxygen species, inflammation, and release of mitochondrial DNA damage (mtDNA) that, via TLRs, promote a pro-oxidative and inflammatory environment in the placental vasculature that result in endothelial dysfunction that culminates in preeclampsia. To investigate this hypothesis, Dr. McIntosh will 1) determine whether placental hypoxia induces mtDNA damage using placental samples within a hypoxic environment and 2) test whether heightened mtDNA damage in vessels from preeclamptic placentas is responsible for impaired endothelial dependent dilation via toll-like receptors. Videomicroscopy and wire myography will be used to test vasodilator capacity, flow mediated dilation (FMD), and altered FMD as a result of heightened mtDNA in vessels from placentas in those with preeclampsia and whether that could be reversed by inhibiting toll-like receptors. These studies may provide a mechanism that can ultimately be targeted for therapeutic intervention. Through Dr. McIntosh?s proposed career development plan, she will become an expert in the vascular biology of the human placental microcirculation and mitochondrial dysfunction. These skills will position Dr. McIntosh to develop her R01 application and ultimately become a leader in the field.